Kulathu Lab

 

Regulation of protein degradation:

 

Timely elimination of misfolded and damaged proteins is essential to prevent the formation of toxic protein aggregates, the underlying cause of numerous proteinopathies such as Alzheimer’s and Parkinson’s disease. Proteins to be eliminated are ubiquitylated and subsequently targeted for degradation. How a cell determines whether a protein should be degraded, and the choice of how it is degraded, i.e. by the ubiquitin proteasome system or by autophagy, is unclear. The text book model illustrates that when a protein is tagged with K48-linked polyubiquitin, that protein is degraded by the proteasome. Recent work has shown that other signals such as branched ubiquitin chains containing K48 and K11 linkages function as specialized degradation signals, challenging the simplistic conventional model. We have recently discovered K48 chains to exist as heterotypic chains that also contain K29 linkages. Whether such a heterotypic chain provides a different signal for protein degradation remains unknown. Several aspects of protein degradation remain unclear.

For instance, what ubiquitin signals target proteins for degradation? Are some signals better than others in signalling destruction?

How is this process dynamically regulated, i.e., can signals be edited by DUBs and E3s to be a better degradation signal or alternatively reversed to rescue proteins from degradation?

And how is protein degradation achieved at different subcellular localizations?

 

We recently discovered a new family of Deubiquitinating enzymes that we named MINDY (MIU containing novel DUB family). MINDY DUBs are highly conserved and present in all eukaryotes. Strikingly, all MINDY DUBs identified thus far are highly selective at cleaving K48-linked polyubiquitin. We are therefore exploring the cellular roles of MINDY DUBs in regulating protein degradation.

Since decline in protein homeostasis contributes to ageing and age-related disorders, there is an urgent need to understand how protein degradation is regulated in cells to develop strategies to boost proteostasis. By addressing fundamental questions, I anticipate our research will unravel hitherto unknown players, mechanisms and paradigms that will improve our understanding of how proteins are degraded and how they go wrong in disease.

 

 

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